<p>Current first-line antidepressants, such as selective serotonin reuptake inhibitors (SSRI), often present a delayed onset of action and fail to effectively treat a large proportion of patients, leaving a gap in the treatment of mood disorders. Psychedelics have recently emerged as promising alternatives due to their ability to produce fast-acting antidepressant effects through neuroplastic adaptations, but their hallucinogenic properties remain a major obstacle to their widespread therapeutic use. In this study, we characterized a novel class of halogenated DMT derivatives—5-F-DMT, 5-Cl-DMT, and 5-Br-DMT—for their pharmacological activity, behavioral effects, and therapeutic potential. Using a combination of in vitro assays, in silico modeling, and in vivo behavioral and gene expression studies, we found that halogen substitution at the 5-position modulates receptor affinity and selectivity across key serotonin (5-HT) receptors (5-HT1A/2 A/2B/2CR) and transporter (SERT). Notably, 5-Br-DMT was found to activate 5-HT2AR but did not induce the head twitch response (HTR) in mice, suggesting non-hallucinogenic activity. Furthermore, 5-Br-DMT upregulated immediate early genes (IEGs) associated with neuroplasticity in the mouse prefrontal cortex and hippocampus (<i>Arc, Egr-1, -2 and -3</i>) and promoted dendritic growth in cortical neurons. In a mouse model of stress-induced depression, a single administration (10 mg/kg, i.p.) of 5-Br-DMT resulted in a significant reduction in depressive-like behavior, reflecting rapid antidepressant effects. Collectively, our results highlight 5-Br-DMT as a non-hallucinogenic psychoplastogen with antidepressant properties, supporting its potential as a prototypical candidate for further study. Moreover, the evaluation and biological characterization of the halogenated DMT derivatives offers valuable information on structure-activity relationships that may guide the design of future therapeutic compounds.</p>